review article role of glutathione in cancer progression...

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2013, Article ID 972913, 10 pageshttp://dx.doi.org/10.1155/2013/972913

Review ArticleRole of Glutathione in Cancer Progression and Chemoresistance

Nicola Traverso, Roberta Ricciarelli, Mariapaola Nitti,Barbara Marengo, Anna Lisa Furfaro, Maria Adelaide Pronzato,Umberto Maria Marinari, and Cinzia Domenicotti

Department of Experimental Medicine, Section of General Pathology, Via LB Alberti 2, 16132 Genoa, Italy

Correspondence should be addressed to Cinzia Domenicotti; [email protected]

Received 22 January 2013; Revised 26 April 2013; Accepted 29 April 2013

Academic Editor: Donald A. Vessey

Copyright © 2013 Nicola Traverso et al.This is an open access article distributed under the Creative CommonsAttribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, andapoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases includingcancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility tooxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance tooxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effectsin the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.

1. Introduction

Reactive oxygen species (ROS) are physiologically producedby aerobic cells [1] and their production increases under con-ditions of cell injury [2]. Physiological levels of ROS mediatecrucial intracellular signaling pathways and are essential forcell survival. However, an excess of ROS formation generatescell damage and death. To prevent the irreversible celldamage, the increase of ROS induces an adaptive response,consisting in a compensatory upregulation of antioxidantsystems, aimed to restore the redox homeostasis [3].

Oxidative stress has long been implicated in cancerdevelopment and progression [4], suggesting that antioxidanttreatment may provide protection from cancer [5]. On otherhand, prooxidant therapies, including ionizing radiation andchemotherapeutic agents, are widely used in clinics, basedon the rationale that a further oxidative stimulus added tothe constitutive oxidative stress in tumor cells should, infact, cause the collapse of the antioxidant systems, leadingto cell death [6]. However, this latter approach has providedunsatisfactory results in that many primary tumors overex-press antioxidant enzymes at very high levels, leading to aresistance of cancer cells to drug doses [7].

Among the enzymatic systems involved in the mainte-nance of the intracellular redox balance, a main role is played

by GSH [8] that participates, not only in antioxidant defensesystems, but also in many metabolic processes [9].

Elevated GSH levels are observed in various types oftumors, and this makes the neoplastic tissues more resistantto chemotherapy [10, 11]. Moreover, the content of GSH insome tumor cells is typically associated with higher levelsof GSH-related enzymes, such as 𝛾-glutamylcysteine ligase(GCL) and 𝛾-glutamyl-transpeptidase (GGT) activities, aswell as a higher expression of GSH-transporting exportpumps [11, 12]. Therefore, it is not surprising that the GSHsystem has attracted the attention of pharmacologists asa possible target for medical intervention against cancerprogression and chemoresistance.

The main research in this field has been aimed at deplet-ing GSH by a specific inhibition of GCL, a key enzyme ofGSH biosynthesis. In this context, buthionine sulfoximine(BSO) is the most popular GSH-depleting agent studied inboth preclinical and early clinical trials, but limitation onits availability has led to a search for alternatives [13, 14].Recently, GSH analogues have been employed in order tosensitize tumors to cytotoxic effects of anticancer agents, bydepleting GSH-related cytoprotective effects [15].

However, during the last decade, a new approach for theregulation of GSH-utilizing enzymes has emerged. It is alsoevident that many of the antioxidant enzymes are induced

2 Oxidative Medicine and Cellular Longevity

by GSH depletion at the transcriptional level which involvesthe binding of the nuclear factor (erythroid-derived 2)-like2 (Nrf2) transcription factor to the antioxidant responseelement (ARE) in the promoter region of the genes encodingGCL and glutathione S-transferases [16].

2. GSH Biosynthesis

Glutathione (GSH) is a tripeptide formed by glutamic acid,cysteine, and glycine. The glutamic acid forms a particulargamma-peptic bond with cysteine by its gamma glutamylgroup. Two forms of GSH are possible: the reduced form(GSH) which represents the majority of GSH, reachingmillimolar concentration in the intracellular compartment,and the oxidized form (GSSG) that is estimated to be lessthan 1% of the total GSH. Intracellularly, the majority ofGSH is found in the cytosol (about 90%), whilemitochondriacontain nearly 10% and the endoplasmic reticulum containsa very small percentage [17].

The synthesis of GSH from its constituent amino acidsinvolves two ATP-requiring enzymatic steps: (1) the first stepis rate-limiting and catalyzed by GCL which is composedof two subunits: one catalytic (GCLC) and one modifier(GCLM):

GCL

MgATP

L-Glu L-Cys L-Glu L-Cys+

𝛾-glutamylcysteine

MgADP + Pi

(2) The second step is catalyzed by GSH synthetase (GS)[19]:

Gly

MgATP

L-Glu L-CysL-Glu L-Cys Gly

GSHGS

+

𝛾-glutamylcysteine

MgADP + Pi

Although GS is generally thought not to be importantin the regulation of GSH synthesis, accumulating evidencesuggests that GSmay play an important role, at least in certaintissues and/or under stressful conditions [20].

However, under normal physiological conditions, the rateof GSH synthesis is largely determined by two factors, that is,cysteine availability and GCL activity. Cysteine is normallyderived from the diet, protein breakdown and in the liver,from methionine via transsulfuration (conversion of homo-cysteine to cysteine). Cysteine differs from other amino acidsbecause its sulfhydryl form, cysteine, is predominant insidethe cell whereas its disulfide form, cystine, is predominantoutside the cell [21].

3. Glutathione Functions

The chemical structure of GSH determines its potential func-tions, and its broad distribution among all living organismsreflects its important biological role. Amajor function ofGSHis the detoxification of xenobiotics and some endogenouscompounds. These substances are electrophiles and form

conjugates with GSH, either spontaneously or enzymatically,in reactions catalyzed by GSH-S-transferases (GST) [22].Human GSTs are divided into two distinct family mem-bers: the membrane-bound microsomal and cytosolic familymembers. The conjugates formed are usually excreted in thebile, but can also undergo modification to mercapturic acid.

Another important GSH function is the maintenance ofthe intracellular redox balance and the essential thiol statusof proteins [21].

The reaction with the protein is as follows:

Protein-SSG + GSH←→ Protein-SH + GSSG. (1)

The equilibrium of this reaction depends on the con-centrations of GSH and GSSG. The reversible thiolationof proteins is known to regulate several metabolic pro-cesses including enzyme activity, transport activity, signaltransduction and gene expression through redox-sensitivenuclear transcription factors such as AP-1, NF-kappaB (NF-kB) and p53 [21, 23]. In fact, DNA-binding activity oftranscription factors often involves critical Cys residues, andthe maintenance of these residues in a reduced form, atleast in the nuclear compartment, is necessary [24]. AP-1is a transcription factor related to tumor promotion [25],and its DNA-binding activity can be diminished if Cys-252 is oxidized [26]. Tumor suppressor p53, known as the“guardian of the genome,” contains 12 Cys residues in itsamino acid sequence [27], and oxidation of some of theseinhibits p53 function [28]. Moreover, GSH performs anantioxidant function (Figure 1).

In addition, storage of cysteine is one of the mostimportant functions of GSH because cysteine is extremelyunstable extracellularly and rapidly autooxidizes to cystine ina process that produces potentially toxic oxygen-free radicals[29]. The 𝛾-glutamyl cycle allows GSH to be the main sourceof cysteine (Figure 2).

4. Role of GSH in Regulating CancerDevelopment and Growth

In many normal and malignant cells, increased GSH level isassociatedwith a proliferative response and is essential for cellcycle progression [30, 31]. The molecular mechanism of howGSHmodulates cell proliferation remains largely speculative.A key mechanism for GSH’s role in DNA synthesis relatesto the maintenance of reduced glutaredoxin or thioredoxin,which is required for the activity of ribonucleotide reductase,the rate-limiting enzyme in DNA synthesis [32].

Furthermore, in liver cancer and metastatic melanomacells, GSH status is correlated with growth [33–35] andit has also been demonstrated that a direct correlationbetween GSH levels associated with cellular proliferation andmetastatic activity exists [33]. In fact, intrasplenic inoculationof B16 melanoma (B16M) cells into C57BL/6J syngenic miceinduced metastatic foci formation by colonizing differentorgans. However, the number and size of metastases weremuch higher when B16M cells with high GSH content wereinoculated in vivo [33]. A high percentage of tumor cells withhigh GSH content were able to survive in the presence of

Oxidative Medicine and Cellular Longevity 3

Catalase

Peroxisome

ROOH2 GSH

GSSG

GPx or GST

2 GSH

GSSG

GPx GSSGreductase

NADPH

P-SH P-SSG

GSSG

H2O2

NADP+

H2O + O2

ROH + H2O

H2O2

H2O

Figure 1: Antioxidant function of GSH.The hydrogen peroxide, produced during the aerobic metabolism, can be metabolized in the cytosolby GSH peroxidase (GPx) and catalase in peroxisomes. In order to prevent oxidative damage, the GSSG is reduced to GSH byGSSG reductaseat the expense of NADPH, forming a redox cycle [17]. Organic peroxides can be reduced both by GPx andGSH-transferase (GST). In extremeconditions of oxidative stress, the ability of the cell to reduceGSSG toGSHmay be less, inducing the accumulation of GSSGwithin the cytosol.In order to avoid a shift in the redox equilibrium, the GSSG can be actively transported out of the cell or react with protein sulfhydryl groups(PSH) and form mixed disulfides (PSSG).

GSH

GSH

aa

DP

Cysteinyl-glycine

aa5-Oxoproline

GGT

Glycine Cysteine

CysteineProtein

Sulfate + taurine𝛾-Glutamyl-aa

𝛾-Glutamyl-aa

Figure 2: 𝛾-Glutamyl cycle. In the 𝛾-glutamyl cycle, GSH is released from the cell and the ectoenzyme GGT transfers the 𝛾-glutamyl moietyof GSH to an amino acid (aa, the best acceptor being cysteine), forming 𝛾-glutamyl-aa and cysteinyl-glycine. The 𝛾-glutamyl-amino acid canthen be transported back into the cell and once inside can be further metabolized to release the aa and 5-oxoproline, which can be convertedto glutamate and used for GSH synthesis. Cysteinyl-glycine is broken down by dipeptidase (DP) to generate cysteine and glycine. Once insidethe cell, the majority of cysteine is incorporated into GSH, some being incorporated into protein, and some degraded into sulfate and taurine[18].

the nitrosative and oxidative stress, thereby representing themain task force in the metastatic invasion [36]. Therefore,it is plausible that maintenance of high intracellular levelsof GSH could be critical for the extravascular growth ofmetastatic cells. Moreover, maintenance of mitochondrialGSH homeostasis may be a limiting factor for the survivalof metastatic cells in the immediate period following intra-sinusoidal arrest and interaction with activated vascularendothelial cells. Mitochondrial dysfunction is a commonevent in the mechanism leading to cell death [37], and,recently, it has been found to be an essential step for the killingof non-small-cell lung (NSCLC) carcinomas which are resis-tant to conventional treatments [38].Thus, the impairment ofGSH uptake by mitochondria may be important to sensitizeinvasive cancer cells to prooxidant compounds capable ofactivating the cell death mechanism.

As previously reported, GSH is effluxed by cells throughGGT-mediated metabolism, allowing a “GSH-cycle” to takeplace, which is implicated in tumor development [39]. Infact, GGT-positive foci were found in animals exposed toprooxidant carcinogens, suggesting the hypothesis of GGTas an early marker of neoplastic transformation [40, 41].Moreover, increased levels of GGT have been observed incancers of the ovaries [42], colon [43], liver [44], melanoma[45], and leukemias [46]. In studies on melanoma cells invitro and in vivo, elevated GGT activity has been foundto accompany an increased invasive growth [45, 47, 48],and a positive correlation has been described between GGTexpression and unfavourable prognostic signs in humanbreast cancer [49].

The prooxidant activity of GGT has also recently beenshown to promote the iron-dependent oxidative damage of


DNA in GGT-transfected melanoma cells, thus potentiallycontributing to genomic instability and an increased muta-tion risk in cancer cells [50]. GGT/GSH-dependent prooxi-dant reactions has been shown to exert an antiproliferativeaction in ovarian cancer cells [51], while other studies inU937lymphoma cells have shown that basal GGT-dependent pro-duction of hydrogen peroxide can represent an antiapoptoticsignal [52].Themodulatory effects of GGT-mediated prooxi-dant reactions could contribute to the resistance phenotypeof GGT-expressing cancer cells by regulating both signaltransduction pathways involved in proliferation/apoptosisbalance, as well as by inducing protective adaptations in thepool of intracellular antioxidants.

5. GSH Depletion as an ExperimentalApproach to SensitizeTumor Cells to Therapy

Cancer cell lines containing low GSH levels have beendemonstrated to be much more sensitive than control cellsto the effect of irradiation [18]. In fact, GSH depletionobtained by BSO, the irreversible inhibitor of GCL, is themost frequently used approach and it is associated withmanychemotherapeutic agents [53–57]. However, molecular sig-naling of BSO-induced apoptosis is poorly understood, and,recently, it has been demonstrated that in different leukaemiaand lymphoma cells, the death receptor-mediated apoptoticpathway, induced by arsenic trioxide plus BSO, is triggeredvia JNK activation [58]. Moreover, in neuroblastoma cellssusceptible to BSO treatment, DNA damage and apoptosiswas triggered via PKC-𝛿 activation and ROS production [59,60].

In fact, BSO in combination with melphalan [14, 61],is currently undergoing clinical evaluation in childrenwith neuroblastoma (NCT00002730; NCT00005835) and inpatients with persistent or recurrent stage III malignantmelanoma (NCT00661336). Recently, it has been demon-strated that a combination of azathioprine with BSO is usefulfor localized treatment of human hepatocellular carcinoma[62].

Therefore, BSO clinical use is restricted by its shorthalf-life, with the consequent need for prolonged infusionsresulting in its nonselective effect of GSH depletion on bothnormal and malignant cells [63].

6. Role of GSH in Chemoresistance

The increase in GSH levels, GCL activity and GCLC genetranscription is associated with drug resistance in tumor cells[64, 65].

The increase inGSH is amajor contributing factor to drugresistance by binding to or reacting with, drugs, interactingwith ROS, preventing damage to proteins or DNA, or byparticipating in DNA repair processes. In melanoma cells,GSH depletion and GGT inhibition significantly increasedcytotoxicity via oxidative stress [66]. In addition, it hasbeen demonstrated that GGT-overexpressing cells were more

resistant to hydrogen peroxide [67] and chemotherapics, suchas doxorubicin [68], cisplatin [64], and 5-fluorouracil [69].

Moreover, it has been found that the human multidrugresistance protein (MRP), a member of the superfamily ofATP-binding cassette membrane transporters, can lead toresistance to multiple classes of chemotherapeutic agents [70,71]. Several studies have shown coordinated overexpressionof GCLC and MRP in drug-resistant tumor cell lines, inhuman colorectal tumors and in human lung cancer speci-mens after platinum exposure [70, 71].

Three mechanisms have been proposed for the role ofGSH in regulating cisplatin (CDDP) resistance: (i) GSH mayserve as a cofactor in facilitating MRP2-mediated CDDPefflux in mammalian cells; (ii) GSH may serve as a redox-regulating cytoprotector based on the observations thatmanyCDDP-resistant cells overexpress GSH and 𝛾-GCS; and (iii)GSH may function as a copper (Cu) chelator.

Moreover, overexpression of specific GSTs can also affectchemoresistance, whereas polymorphisms that decrease GSTactivity are associated with a high risk of developing can-cer [72]. An elevated expression of GSTs, combined withhigh GSH levels, can increase the rate of conjugation anddetoxification of chemotherapy agents, thus reducing theireffectiveness [73]. In addition to the transferase function,GSTs have been shown to form protein-protein interactionswith members of the mitogen activated protein (MAP)kinases. By interacting directly withMAPKs, including c-JunN-terminal kinase 1 (JNK1) and apoptosis signal-regulatingkinase 1 (ASK1), GSTs bind the ligand in a complex structure,preventing interactions with their downstream targets [74].Many anticancer agents induce apoptosis via activation ofMAP kinases, in particular JNK and p38 [75, 76]. This novel,nonenzymatic role for GSTs has direct relevance to the GSToverexpressing phenotypes of many drug-resistant tumors.As an endogenous switch for the control of intracellularsignaling pathways, an elevated expression of GST can alterthe balance of kinases during drug treatment, thereby causinga potential selective advantage for tumor growth.

The promoter regions encoding GSTs and 𝛾GCL possessbinding sites for transcriptional regulators such as NF-kB,AP-1, AP-2, and the Nrf2/Kelch-like ECH-associated protein1 (Keap1) system. After exposure to oxidative stimuli, Nrf2dissociates from Keap1, its negative regulator, and translo-cates into the nucleus where it heterodimerizes with smallMaf proteins [77] and binds to antioxidant responsive ele-ment (ARE) sequences, triggering a cytoprotective adaptativeresponse. This response is characterised by upregulation ofseveral cytoprotective and detoxification genes, includingferritin, GSH-𝑆-reductase (GSR), GST, GCLM, and GCLC,phase-I drug oxidation enzyme NAD(P)H:quinone oxidore-ductase 1 (NQO1), MRP, and heme oxygenase-1 (HO-1) [78,79].

However, in numerous types of cancer, Nrf2 is upregu-lated and takes on a protumoral identity since the above-citedcytoprotective genes, not only give tumors an advantage, butalso lead to drug resistance [80–82].

To date, numerous mutations have been found of bothKeap1 and Nrf2 in various human cancers resulting in theconstitutive expression of prosurvival genes. Most of Nrf2


somatic mutations have led to the impairment of their recog-nition site for Keap1, which then has led to the continuousactivation of Nrf2. Moreover, it has been observed that theprognosis of patients with either Nrf2 or Keap1 mutations ismuch lower than patients with no mutation [83].

Among Nrf2-regulated genes, HO-1 is the most wellknown as a stress protein that can have both antioxidative andanti-inflammatory effects [84]. It catalyzes the rate-limitingstep in the catabolism of the prooxidant heme to carbonmonoxide, biliverdin, and free iron [85].

Recent experimental evidence has shown the involve-ment of HO-1 in cancer cell biology. On one hand, HO-1 protects healthy cells from transformation into neoplasticcells by counteracting ROS-mediated carcinogenesis and, onthe other hand, HO-1 protects cancer cells, enhancing theirsurvival and their resistance to anticancer treatment [86].In addition, high levels of HO-1 have been observed invarious human solid tumors, such as renal [87], prostatic [88],and pancreatic cancers [89]. Moreover, HO-1 expression intumor cells can be further increased by anticancer treatments(chemo-, radio-, and photodynamic therapy) [90], and it hasbeen hypothesized that HO-1 and its products may have animportant role in the development of a resistant phenotype.In this context, it has been recently demonstrated that BSOand/or the inhibition of the Nrf2/HO-1 axis is able to increasethe sensitivity of neuroblastoma cells to etoposide [91, 92].

7. Therapeutic Potential of GSH andGSH-Modulating Agents

The modulation of the GSH-based antioxidant redox system(GRS), the major determinant of the cellular redox status[93], might represent a promising therapeutic strategy forovercoming cancer cell progression and chemoresistance.

However, GSH itself cannot be administered clinicallywith any effect, and for this reason, a variety of precursors orchemically modified analogues have been generated in orderto mimic glutathione’s various physiological or pharmaco-logical effects.N-acetylcysteine (NAC;Mucomyst) representsthe earlier GSH analogue, and YM737, a monoester of GSH,recently discovered, has been favourably compared to NAC[94]. AnotherGSHanalogue approach is cysteine-substitutedS-nitrosoglutathione [95].

Since abundant levels of GST [96] have been identifiedin resistant tumors, GSH analogues, that differentially inhibitGST isoforms, have been developed. Telcyta (TLK-286) isa GSH analogue utilized in combination with cytotoxicchemotherapies such as platinum, taxanes, and anthracy-clines in a variety of tumors with very high levels ofglutathione 𝑆-transferase pi-1-gene (GST-P1-1) [97]. Telintra(TLK199) is another small molecule inhibitor of GST-P1-1developed for the potential prevention of myelosuppressionin blood diseases, namely, myelodysplastic syndrome [98].After a phase 1 clinical trial [99] and a phase 2 using an oralformulation, TLK199 appeared to be well tolerated and withsome efficacy in the myeloplastic syndrome treatment [100].

In addition, the implication of GGT activity in theresistance phenotype of cancer cells suggests a potential use ofGGT inhibitors associated with chemotherapeutics in order

to deplete intracellular GSH and/or to inhibit extracellulardrug detoxification. Different GGT inhibitors are known[101–103], but, unfortunately, these molecules are toxic andcannot be used in humans.

Moreover, drugs that target S-glutathionylation havedirect anticancer effects since they act on a wide range ofsignalling pathways [57]. Among the agents thatmediate theireffects through S-glutathionylation, NOV-002 has been mostextensively studied, with a phase III trial (NCT00347412)completed in advancedNSCLC [104], and data available fromphase II trials in breast and ovarian cancers [105]. NOV-002 is a product containing oxidized glutathione that alterthe GSH :GSSG ratio and induces S-glutathionylation [106].NOV-002-induced S-glutathionylation has been shown tohave inhibitory effects on proliferation, survival, and invasionof myeloid cell lines and significantly increased the efficacy ofcyclophosphamide chemotherapy in amurinemodel of coloncancer [107].

In a randomized phase II trial, NOV-002 in combinationwith standard chemotherapy has shown promising effects inpatients with stage IIIb/IV of NSCLC [108]. Positive resultswere also obtained from a phase II trial in patients withneoadjuvant breast cancer therapy [109].

Other therapeutic agents include phenolic antioxidants(𝛼-napthoflavone, butylated hydroxyanisole, and tert-butylhydroquinone), synthetic antioxidants (ethoxyquin, oltipraz,and phorbol esters), triterpenoid analogue (oleanolic acidderivatives, sesquiterpenes), and isothiocyanates (sulfor-aphane). Sulforaphane (SF) is the strongest natural inducerof Nrf2 and phase II detoxifying enzymes and it has a potentanticarcinogenic and chemopreventive effect by inducingapoptosis and cell cycle arrest [110].

On the other hand, the inhibition of Nrf2 signalingmightbe employed to enhance the sensitization of chemoresistanttumors to cytotoxic agents, and in this context, it hasrecently been reported that brusatol, a compound found ina plant extract, acts as inhibitor of this pathway and mayexhibit therapeutic utility [111]. Another effective approach toincreasing cancer cell sensitivity to chemotherapeutic drugswould be to silence bothNrf2 andKeap1 simultaneously [112].Related to Nrf2, a potential target for redox chemotherapy isHO-1. HO-1 inhibitors, including zinc protoporphyrin andmore soluble pegylated derivatives (PEG-ZnPP), have beensuccessfully used to improve chemosensitization of cancercells [113]. Moreover, HO-1 inhibitors administered intra-venously, displayed cytotoxic activity in a murine hypoxicsolid tumor model [114].

Moreover, disulfiram (DSF) does not cause depletion oftotal GSH, but shifts the ratio of GSH/GSSG towards theoxidized state. DSF induces apoptosis of human melanomacells [115], and this apoptogenic effect has encouraged ongo-ing clinical phase I/II studies in humanmetastatic melanoma(NCT00256230).

Arsenic trioxide (As2O3) is a prooxidant chemothera-

peutic compound combined with agents that deplete cellularGSH [116]. As

2O received FDA approval in 2000 for the

treatment of nonacute promyelocytic leukemia and is usedin patients who have relapsed or are refractory to first-lineintervention using retinoid and anthracycline chemotherapy.


As2O inhibits GPx and mitochondrial respiratory func-

tion that leads to increased ROS leakage contributing toantileukemia activity. Another piece of evidence suggests thatthe irreversible inhibition of thioredoxin reductase is thekey mechanism underlying As

2O-induced breast cancer cell

apoptosis [117]. Importantly, As2O3sensitivity is associated

with low levels of GSH in cancer cells and GSH depletion,obtained by BSO or ascorbate treatment, contributes to sen-sitizing cells toward apoptosis [118].The potentiation of As

2O

chemotherapeutic efficacy using BSOwas demonstrated in anorthotopic model of prostate cancer metastasis [119].

8. Conclusions

The modulation of cellular GSH is a double-edged sword,both sides of which have been exploited for potential ther-apeutic benefits [120]. Enhancing the capacity of GSH andits associated enzymes, in order to protect cells from redox-related changes or environmental toxins, represents a persis-tent aim in the search for cytoprotective strategies againstcancer. On the contrary, the strategy of depleting GSH andGSH-related detoxification pathways is aimed at sensitizingcancer cells to chemotherapy, the so-called chemosensitiza-tion [121]. In this context, it has been reported that GSHand GSH enzyme-linked systemmay be a determining factorfor the sensitivity of some tumors to various chemother-apeutic agents. In particular, GST is a relevant parameterfor chemotherapy response, and it may be utilized as auseful biomarker for selecting tumors potentially responsiveto chemotherapeutic regimens.

However, the attempts to deplete GSH have been limitedby the nonselective effects of BSO and have stimulated theresearch of new GCL inhibitors.

Since it is well known that GSH depletion leads tothe upregulation of antioxidant genes, many of which areunder Nrf2 control and, that in several types of tumors,Nrf2 is constitutively activated [122, 123], a new and indirectapproach for cancer therapy may be used to modulatethe Nrf2-ARE pathway. Based on this, Nrf2 creates a newparadigm in cytoprotection, cancer prevention, and drugresistance.

In summary, the involvement of GSH in the carcino-genesis and in the drug resistance of tumor cell is clear,but further studies, aimed at understanding the GSH-drivenmolecular pathways, might be crucial to design new thera-peutic strategies to fight cancer progression and overcomechemoresistance.

Acknowledgments

This work was supported by Grants from PRIN2009M8FKBB 002 and Genoa University, Italy. The authorswould like to thank Ms. Suzanne Patten for language editing.

References

[1] W. Droge, “Free radicals in the physiological control of cellfunction,” Physiological Reviews, vol. 82, no. 1, pp. 47–95, 2002.

[2] M. Valko, D. Leibfritz, J. Moncol, M. T. D. Cronin, M. Mazur,and J. Telser, “Free radicals and antioxidants in normal physi-ological functions and human disease,” International Journal ofBiochemistry and Cell Biology, vol. 39, no. 1, pp. 44–84, 2007.

[3] M. Landriscina, F. Maddalena, G. Laudiero, and F. Esposito,“Adaptation to oxidative stress, chemoresistance, and cell sur-vival,”Antioxidants and Redox Signaling, vol. 11, no. 11, pp. 2701–2716, 2009.

[4] S. P. Hussain, L. J. Hofseth, and C. C. Harris, “Radical causes ofcancer,”Nature Reviews Cancer, vol. 3, no. 4, pp. 276–285, 2003.

[5] C.M. Cabello,W. B. Bair III, andG. T.Wondrak, “Experimentaltherapeutics: targeting the redox Achilles heel of cancer,” Cur-rent Opinion in Investigational Drugs, vol. 8, no. 12, pp. 1022–1037, 2007.

[6] P. S. Lecane, M. W. Karaman, M. Sirisawad et al., “Motexafingadolinium and zinc induce oxidative stress responses andapoptosis in B-cell lymphoma lines,” Cancer Research, vol. 65,no. 24, pp. 11676–11688, 2005.

[7] J. Wang and J. Yi, “Cancer cell killing via ROS: to increase ordecrease, that is a question,” Cancer Biology andTherapy, vol. 7,no. 12, pp. 1875–1884, 2008.

[8] A. Meister, “Glutathione metabolism,”Methods in Enzymology,vol. 251, pp. 3–7, 1995.

[9] H. Sies, “Glutathione and its role in cellular functions,” FreeRadical Biology andMedicine, vol. 27, no. 9-10, pp. 916–921, 1999.

[10] P. Calvert, K. S. Yao, T. C. Hamilton, and P. J. O’Dwyer, “Clinicalstudies of reversal of drug resistance based on glutathione,”Chemico-Biological Interactions, vol. 111-112, pp. 213–224, 1998.

[11] J. M. Estrela, A. Ortega, and E. Obrador, “Glutathione in cancerbiology and therapy,” Critical Reviews in Clinical LaboratorySciences, vol. 43, no. 2, pp. 143–181, 2006.

[12] M. L. O’Brien and K. D. Tew, “Glutathione and related enzymesin multidrug resistance,” European Journal of Cancer A, vol. 32,no. 6, pp. 967–978, 1996.

[13] O. W. Griffith, “Mechanism of action, metabolism, and toxicityof buthionine sulfoximine and its higher homologs, potentinhibitors of glutathione synthesis,” The Journal of BiologicalChemistry, vol. 257, no. 22, pp. 13704–13712, 1982.

[14] P. J. O’Dwyer, T. C. Hamilton, F. P. LaCreta et al., “Phase I trialof buthionine sulfoximine in combination with melphalan inpatients with cancer,” Journal of Clinical Oncology, vol. 14, no. 1,pp. 249–256, 1996.

[15] J. H.Wu and G. Batist, “Glutathione and glutathione analogues,therapeutic potentials,” Biochimica et Biophysica Acta, vol. 1830,no. 5, pp. 3350–3353, 2012.

[16] T. Nguyen, P. Nioi, and C. B. Pickett, “The Nrf2-antioxidantresponse element signaling pathway and its activation byoxidative stress,” The Journal of Biological Chemistry, vol. 284,no. 20, pp. 13291–13295, 2009.

[17] S. C. Lu, “Regulation of glutathione synthesis,” MolecularAspects of Medicine, vol. 30, no. 1-2, pp. 42–59, 2009.

[18] A.Meister, “Glutathione deficiency produced by inhibition of itssynthesis, and its reversal; applications in research and therapy,”Pharmacology andTherapeutics, vol. 51, no. 2, pp. 155–194, 1991.

[19] L. Oppenheimer, V. P. Wellner, O. W. Griffith, and A. Meister,“Glutathione synthetase. Purification from rat kidney andmapping of the substrate binding sites,”The Journal of BiologicalChemistry, vol. 254, no. 12, pp. 5184–5190, 1979.

[20] J. L. Luo, F. Hammarqvist, K. Andersson, and J. Wernerman,“Surgical trauma decreases glutathione synthetic capacity inhuman skeletal muscle tissue,” American Journal of Physiology,vol. 275, no. 2, part 1, pp. E359–E365, 1998.


[21] S. C. Lu, “Regulation of hepatic glutathione synthesis: currentconcepts and controversies,”The FASEB Journal, vol. 13, no. 10,pp. 1169–1183, 1999.

[22] A. Meister, “On the discovery of glutathione,” Trends in Bio-chemical Sciences, vol. 13, no. 5, pp. 185–188, 1988.

[23] D.M. Townsend, K. D. Tew, andH. Tapiero, “The importance ofglutathione in human disease,” Biomedicine and Pharmacother-apy, vol. 57, no. 3, pp. 145–155, 2003.

[24] Y. Morel and R. Barouki, “Repression of gene expression byoxidative stress,” Biochemical Journal, vol. 342, part 3, pp. 481–496, 1999.

[25] C. K. Sen and L. Packer, “Antioxidant and redox regulation ofgene transcription,” The FASEB Journal, vol. 10, no. 7, pp. 709–720, 1996.

[26] D. Nikitovic, A. Holmgren, and G. Spyrou, “Inhibition of AP-1 DNA binding by nitric oxide involving conserved cysteineresidues in Jun and Fos,” Biochemical and Biophysical ResearchCommunications, vol. 242, no. 1, pp. 109–112, 1998.

[27] R. Rainwater, D. Parks, M. E. Anderson, P. Tegtmeyer, and K.Mann, “Role of cysteine residues in regulation of p53 function,”Molecular and Cellular Biology, vol. 15, no. 7, pp. 3892–3903,1995.

[28] H. H. Wu and J. Momand, “Pyrrolidine dithiocarbamateprevents p53 activation and promotes p53 cysteine residueoxidation,”The Journal of Biological Chemistry, vol. 273, no. 30,pp. 18898–18905, 1998.

[29] A. Meister and M. E. Anderson, “Glutathione,” Annual Reviewof Biochemistry, vol. 52, pp. 711–760, 1983.

[30] J. P. Messina and D. A. Lawrence, “Cell cycle progressionof glutathione-depleted human peripheral blood mononuclearcells is inhibited at S phase,” Journal of Immunology, vol. 143, no.6, pp. 1974–1981, 1989.

[31] S. C. Lu and J. L. Ge, “Loss of suppression of GSH synthesisat low cell density in primary cultures of rat hepatocytes,”American Journal of Physiology, vol. 263, no. 6, part 1, pp. C1181–C1189, 1992.

[32] A.Holmgren, “Regulation of ribonucleotide reductase,”CurrentTopics in Cellular Regulation, vol. 19, pp. 47–76, 1981.

[33] J. Carretero, E. Obrador, M. J. Anasagasti, J. J. Martin, F. Vidal-Vanaclocha, and J. M. Estrela, “Growth-associated changes inglutathione content correlate with liver metastatic activity ofB16 melanoma cells,” Clinical and Experimental Metastasis, vol.17, no. 7, pp. 567–574, 1999.

[34] Z. Z. Huang, C. Chen, Z. Zeng et al., “Mechanism and signif-icance of increased glutathione level in human hepatocellularcarcinoma and liver regeneration,” The FASEB Journal, vol. 15,no. 1, pp. 19–21, 2001.

[35] B. Marengo, C. D. Ciucis, R. Ricciarelli et al., “DNA oxidativedamage of neoplastic rat liver lesions,” Oncology Reports, vol.23, no. 5, pp. 1241–1246, 2010.

[36] J. Carretero, E. Obrador, J. M. Esteve et al., “Tumoricidalactivity of endothelial cells: inhibition of endothelial nitric oxideproduction abrogates tumor cytotoxicity induced by hepaticsinusoidal endothelium in response to B16 melanoma adhesionin vitro,”The Journal of Biological Chemistry, vol. 276, no. 28, pp.25775–25782, 2001.

[37] P. Costantini, E. Jacotot, D. Decaudin, and G. Kroemer,“Mitochondrion as a novel target of anticancer chemotherapy,”Journal of the National Cancer Institute, vol. 92, no. 13, pp. 1042–1053, 2000.

[38] B. Joseph, P. Marchetti, P. Formstecher, G. Kroemer, R. Lewen-sohn, and B. Zhivotovsky, “Mitochondrial dysfunction is anessential step for killing of non-small cell lung carcinomasresistant to conventional treatment,”Oncogene, vol. 21, no. 1, pp.65–77, 2002.

[39] A. Pompella, A. Corti, A. Paolicchi, C. Giommarelli, and F.Zunino, “𝛾-Glutamyltransferase, redox regulation and cancerdrug resistance,” Current Opinion in Pharmacology, vol. 7, no.4, pp. 360–366, 2007.

[40] A. Pompella, V. De Tata, A. Paolicchi, and F. Zunino, “Expres-sion of 𝛾-glutamyltransferase in cancer cells and its significancein drug resistance,” Biochemical Pharmacology, vol. 71, no. 3, pp.231–238, 2006.

[41] M. W. Roomi, K. Gaal, Q. X. Yuan et al., “Preneoplastic livercell foci expansion induced by thioacetamide toxicity in drug-primed mice,” Experimental and Molecular Pathology, vol. 81,no. 1, pp. 8–14, 2006.

[42] M. H. Hanigan, H. F. Frierson Jr., J. E. Brown, M. A. Lovell,and P. T. Taylor, “Human ovarian tumors express 𝛾-glutamyltranspeptidase,” Cancer Research, vol. 54, no. 1, pp. 286–290,1994.

[43] J. Murata, P. Ricciardi-Castagnoli, P. D. Mange, F. Martin, andL. Juillerat-Jeanneret, “Microglial cells induce cytotoxic effectstoward colon carcinoma cells: measurement of tumor cytotoxi-city with a gamma-glutamyl transpeptidase assay,” InternationalJournal of Cancer, vol. 70, no. 2, pp. 169–174, 1997.

[44] M. Tsutsumi, D. Sakamuro, A. Takada, S. C. Zang, T. Furukawa,and N. Taniguchi, “Detection of a unique 𝛾-glutamyl transpep-tidase messenger RNA species closely related to the develop-ment of hepatocellular carcinoma in humans: a new candidatefor early diagnosis of hepatocellular carcinoma,” Hepatology,vol. 23, no. 5, pp. 1093–1097, 1996.

[45] R. Supino, E.Mapelli, O. Sanfilippo, and L. Silvestro, “Biologicaland enzymatic features of human melanoma clones with differ-ent invasive potential,” Melanoma Research, vol. 2, no. 5-6, pp.377–384, 1992.

[46] M. Tager, A. Ittenson, A. Franke, A. Frey, H. G. Gassen, andS. Ansorge, “𝛾-glutamyl transpepsidase-cellular expression inpopulations of normal human mononuclear cells and patientssuffering from leukemias,” Annals of Hematology, vol. 70, no. 5,pp. 237–242, 1995.

[47] J. A. Prezioso, N. Wang, L. Duty, W. D. Bloomer, and E.Gorelik, “Enhancement of pulmonarymetastasis formation and𝛾-glutamyltranspeptidase activity in B16 melanoma induced bydifferentiation in vitro,” Clinical and Experimental Metastasis,vol. 11, no. 3, pp. 263–274, 1993.

[48] E. Obrador, J. Carretero, A. Ortega et al., “𝛾-glutamyl transpep-tidase overexpression increases metastatic growth of B16melanoma cells in the mouse liver,” Hepatology, vol. 35, no. 1,pp. 74–81, 2002.

[49] S. Bard, P. Noel, F. Chauvin, and G. Quash, “𝛾-glutamyltranspeptidase activity in human breast lesions:an unfavourable prognostic sign,” British Journal of Cancer, vol.53, no. 5, pp. 637–642, 1986.

[50] A. Corti, T. L. Duarte, C. Giommarelli et al., “Membranegamma-glutamyl transferase activity promotes iron-dependentoxidative DNA damage in melanoma cells,”Mutation Research,vol. 669, no. 1-2, pp. 112–121, 2009.

[51] P. Perego, A. Paolicchi, R. Tongiani et al., “The cell-specificanti-proliferative effect of reduced glutathione is mediated by


gamma-glutamyl transpeptidase-dependent extracellular pro-oxidant reactions,” International Journal of Cancer, vol. 71, no.2, pp. 246–250, 1997.

[52] B. del Bello, A. Paolicchi, M. Comporti, A. Pompella, andE. Maellaro, “Hydrogen peroxide produced during 𝛾-glutamyltranspeptidase activity is involved in prevention of apoptosisand maintenance of proliferation in U937 cells,” The FASEBJournal, vol. 13, no. 1, pp. 69–79, 1999.

[53] U. Reber,U.Wullner,M.Trepel et al., “Potentiation of treosulfantoxicity by the glutathione-depleting agent buthionine sulfox-imine in human malignant glioma cells. The role of BCL-2,”Biochemical Pharmacology, vol. 55, no. 3, pp. 349–359, 1998.

[54] C. P. Anderson, J. M. Tsai, W. E. Meek et al., “Depletion ofglutathione by buthionine sulfoximine is cytotoxic for humanneuroblastoma cell lines via apoptosis,” Experimental CellResearch, vol. 246, no. 1, pp. 183–192, 1999.

[55] C. Friesen, Y. Kiess, and K. M. Debatin, “A critical role ofglutathione in determining apoptosis sensitivity and resistancein leukemia cells,” Cell Death and Differentiation, vol. 11,supplement 1, pp. S73–S85, 2004.

[56] M. D’Alessio, C. Cerella, C. Amici et al., “Glutathione depletionup-regulates Bcl-2 in BSO-resistant cells,” The FASEB Journal,vol. 18, no. 13, pp. 1609–1611, 2004.

[57] G. T.Wondrak, “Redox-directed cancer therapeutics:molecularmechanisms and opportunities,” Antioxidants and Redox Sig-naling, vol. 11, no. 12, pp. 3013–3069, 2009.

[58] D. Chen, R. Chan, S. Waxman, and Y. Jing, “Buthionine sul-foximine enhancement of arsenic trioxide-induced apoptosis inleukemia and lymphoma cells is mediated via activation of c-JunNH

2-terminal kinase andup-regulation of death receptors,”

Cancer Research, vol. 66, no. 23, pp. 11416–11423, 2006.[59] C. Domenicotti, B. Marengo, D. Verzola et al., “Role of PKC-𝛿 activity in glutathione-depleted neuroblastoma cells,” FreeRadical Biology and Medicine, vol. 35, no. 5, pp. 504–516, 2003.

[60] B. Marengo, C. de Ciucis, R. Ricciarelli et al., “PKC𝛿 sensitizesneuroblastoma cells to L-buthionine-sulfoximine and etoposideinducing reactive oxygen species overproduction and DNAdamage,” PLoS ONE, vol. 6, no. 2, Article ID e14661, 2011.

[61] H. H. Bailey, G. Ripple, K. D. Tutsch et al., “Phase I study ofcontinuous-infusion L-S,R-buthionine sulfoximine with intra-venous melphalan,” Journal of the National Cancer Institute, vol.89, no. 23, pp. 1789–1796, 1997.

[62] B. Hernandez-Breijo, J. Monserrat, S. Ramirez-Rubio et al.,“Preclinical evaluation of azathioprine plus buthionine sulfox-imine in the treatment of human hepatocarcinoma and coloncarcinoma,” World Journal of Gastroenterology, vol. 17, no. 34,pp. 3899–3911, 2011.

[63] D. Hamilton, H. W. Jian, and G. Batist, “Structure-basedidentification of novel human 𝛾-glutamylcysteine synthetaseinhibitors,”Molecular Pharmacology, vol. 71, no. 4, pp. 1140–1147,2007.

[64] A. K. Godwin, A. Meister, P. J. O’Dwyer, Chin Shiou Huang, T.C. Hamilton, and M. E. Anderson, “High resistance to cisplatinin human ovarian cancer cell lines is associated with markedincrease of glutathione synthesis,” Proceedings of the NationalAcademy of Sciences of the United States of America, vol. 89, no.7, pp. 3070–3074, 1992.

[65] R. T. Mulcahy, S. Untawale, and J. J. Gipp, “Transcriptional up-regulation of 𝛾-glutamylcysteine synthetase gene expression inmelphalan-resistant human prostate carcinoma cells,” Molecu-lar Pharmacology, vol. 46, no. 5, pp. 909–914, 1994.

[66] M. Benlloch, A. Ortega, P. Ferrer et al., “Acceleration of glu-tathione efflux and inhibition of 𝛾- glutamyltranspeptidase sen-sitize metastatic B16 melanoma cells to endothelium-inducedcytotoxicity,”The Journal of Biological Chemistry, vol. 280, no. 8,pp. 6950–6959, 2005.

[67] M. Shi, E. Gozal, H. A. Choy, and H. J. Forman, “Extracel-lular glutathione and 𝛾-glutamyl transpeptidase preent H

2O2-

induced injury by 2,3-dimethoxy-1,4-naphthoquinone,” FreeRadical Biology and Medicine, vol. 15, no. 1, pp. 57–67, 1993.

[68] S. N. Hochwald, D. M. Rose, M. F. Brennan, and M. E. Burt,“Elevation of glutathione and related enzyme activities in high-grade and metastatic extremity soft tissue sarcoma,” Annals ofSurgical Oncology, vol. 4, no. 4, pp. 303–309, 1997.

[69] A. D. Lewis, J. D. Hayes, and C. R. Wolf, “Glutathione andglutathione-dependent enzymes in ovarian adenocarcinomacell lines derived from a patient before and after the onsetof drug resistance: intrinsic differences and cell cycle effects,”Carcinogenesis, vol. 9, no. 7, pp. 1283–1287, 1988.

[70] M. T. Kuo, J. J. Bao,M. Furuichi et al., “Frequent coexpression ofMRP/GS-X pump and 𝛾-glutamylcysteine synthetase mRNA indrug-resistant cells, untreated tumor cells, and normal mousetissues,” Biochemical Pharmacology, vol. 55, no. 5, pp. 605–615,1998.

[71] T. Oguri, Y. Fujiwara, T. Isobe, O. Katoh, H. Watanabe, andM. Yamakido, “Expression of 𝛾-glutamylcysteine synthetase(𝛾-GCS) and Multidrug Resistance-associated Protein (MRP),but not human canalicular Multispecific Organic Anion Trans-porter (cMOAT), genes correlates with exposure of human lungcancers to platinum drugs,” British Journal of Cancer, vol. 77, no.7, pp. 1089–1096, 1998.

[72] G. K. Balendiran, R. Dabur, and D. Fraser, “The role ofglutathione in cancer,” Cell Biochemistry and Function, vol. 22,no. 6, pp. 343–352, 2004.

[73] L. I. McLellan and C. R. Wolf, “Glutathione and glutathione-dependent enzymes in cancer drug resistance,” Drug ResistanceUpdates, vol. 2, no. 3, pp. 153–164, 1999.

[74] V. Adler, Z. Yin, S. Y. Fuchs et al., “Regulation of JNK signalingby GSTp,”The EMBO Journal, vol. 18, no. 5, pp. 1321–1334, 1999.

[75] K. Ono and J. Han, “The p38 signal transduction pathwayactivation and function,” Cellular Signalling, vol. 12, no. 1, pp.1–13, 2000.

[76] B. Marengo, C. G. De Ciucis, R. Ricciarelli et al., “p38MAPKinhibition: a new combined approach to reduce neuroblastomaresistance under etoposide treatment,” Cell Death and Disease,vol. 4, article e589, 2013.

[77] S. Dhakshinamoorthy and A. K. Jaiswal, “Small Maf (MafGand MafK) proteins negatively regulate antioxidant responseelement-mediated expression and antioxidant induction ofthe NAD(P)H:quinone oxidoreductase1 gene,” The Journal ofBiological Chemistry, vol. 275, no. 51, pp. 40134–40141, 2000.

[78] K. Itoh, T. Chiba, S. Takahashi et al., “An Nrf2/small Mafheterodimer mediates the induction of phase II detoxifyingenzyme genes through antioxidant response elements,” Bio-chemical and Biophysical Research Communications, vol. 236,no. 2, pp. 313–322, 1997.

[79] S. A. Rushworth, D. J. MacEwan, and M. A. O’Connell,“Lipopolysaccharide-induced expression of NAD(P)H:quinoneoxidoreductase 1 and heme oxygenase-1 protects against exces-sive inflammatory responses in human monocytes,” Journal ofImmunology, vol. 181, no. 10, pp. 6730–6737, 2008.


[80] T. Ohta, K. Iijima, M. Miyamoto et al., “Loss of Keap1 functionactivates Nrf2 and provides advantages for lung cancer cellgrowth,” Cancer Research, vol. 68, no. 5, pp. 1303–1309, 2008.

[81] T. Jiang, N. Chen, F. Zhao et al., “High levels of Nrf2 deter-mine chemoresistance in type II endometrial cancer,” CancerResearch, vol. 70, no. 13, pp. 5486–5496, 2010.

[82] T. Shibata, A. Kokubu, M. Gotoh et al., “Genetic alterationof Keap1 confers constitutive Nrf2 activation and resistance tochemotherapy in gallbladder cancer,”Gastroenterology, vol. 135,no. 4, pp. 1358.e4–1368.e4, 2008.

[83] T. Shibata, T. Ohta, K. I. Tong et al., “Cancer related mutationsin NRF2 impair its recognition by Keap1-Cul3 E3 ligase andpromote malignancy,” Proceedings of the National Academy ofSciences of the United States of America, vol. 105, no. 36, pp.13568–13573, 2008.

[84] L. E. Otterbein, B. S. Zuckerbraun, M. Haga et al., “Car-bon monoxide suppresses arteriosclerotic lesions associatedwith chronic graft rejection and with balloon injury,” NatureMedicine, vol. 9, no. 2, pp. 183–190, 2003.

[85] L. E. Otterbein, M. P. Soares, K. Yamashita, and F. H. Bach,“Heme oxygenase-1: unleashing the protective properties ofheme,” Trends in Immunology, vol. 24, no. 8, pp. 449–455, 2003.

[86] A. Jozkowicz, H. Was, and J. Dulak, “Heme oxygenase-1 intumors: is it a false friend?” Antioxidants and Redox Signaling,vol. 9, no. 12, pp. 2099–2117, 2007.

[87] A. I. Goodman, M. Choudhury, J. L. Da Silva, M. L. Schwartz-man, and N. G. Abraham, “Overexpression of the heme oxy-genase gene in renal cell carcinoma,” Proceedings of the Societyfor Experimental Biology andMedicine, vol. 214, no. 1, pp. 54–61,1997.

[88] M. D. Maines and P. A. Abrahamsson, “Expression of hemeoxygenase-1 (HSP32) in human prostate: normal, hyperplastic,and tumor tissue distribution,” Urology, vol. 47, no. 5, pp. 727–733, 1996.

[89] P. O. Berberat, Z. Dambrauskas, A. Gulbinas et al., “Inhibitionof heme oxygenase-1 increases responsiveness of pancreaticcancer cells to anticancer treatment,” Clinical Cancer Research,vol. 11, no. 10, pp. 3790–3798, 2005.

[90] D. Nowis, M. Legat, T. Grzela et al., “Heme oxygenase-1protects tumor cells against photodynamic therapy-mediatedcytotoxicity,” Oncogene, vol. 25, no. 24, pp. 3365–3374, 2006.

[91] B. Marengo, E. Balbis, S. Patriarca et al., “GSH loss per sedoes not affect neuroblastoma survival and is not genotoxic,”International Journal ofOncology, vol. 32, no. 1, pp. 121–127, 2008.

[92] A. L. Furfaro, J. R. Macay, B. Marengo et al., “Resistanceof neuroblastoma GI-ME-N cell line to glutathione depletioninvolves Nrf2 and heme oxygenase-1,” Free Radical Biology andMedicine, vol. 52, no. 2, pp. 488–496.

[93] F. Q. Schafer and G. R. Buettner, “Redox environment of thecell as viewed through the redox state of the glutathione disul-fide/glutathione couple,” Free Radical Biology andMedicine, vol.30, no. 11, pp. 1191–1212, 2001.

[94] S. Shibata, K. Tominaga, and S.Watanabe, “Glutathione protectsagainst hypoxic/hypoglycemic decreases in 2-deoxyglucoseuptake and presynaptic spikes in hippocampal slices,” EuropeanJournal of Pharmacology, vol. 273, no. 1-2, pp. 191–195, 1995.

[95] H. Chakrapani, R. C. Kalathur, A. E. Maciag et al., “Synthe-sis, mechanistic studies, and anti-proliferative activity of glu-tathione/glutathione S-transferase-activated nitric oxide pro-drugs,” Bioorganic and Medicinal Chemistry, vol. 16, no. 22, pp.9764–9771, 2008.

[96] G. Batist, A. Tulpule, andB.K. Sinha, “Overexpression of a novelanionic glutathione transferase in multidrug-resistent humanbreast cancer cells,”The Journal of Biological Chemistry, vol. 261,no. 33, pp. 15544–15549, 1986.

[97] J. H. Wu, W. Miao, L. G. Hu, and G. Batist, “Identification andcharacterization of novel Nrf2 inducers designed to target theintervening region of keap1,”Chemical Biology andDrugDesign,vol. 75, no. 5, pp. 475–480, 2010.

[98] D. Hamilton and G. Batist, “TLK-199 Telik,” IDrugs, vol. 8, no.8, pp. 662–669, 2005.

[99] A. Raza, N. Galili, S. Smith et al., “Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), anovel glutathione analog prodrug, in patients with myelodys-plastic syndrome,” Blood, vol. 113, no. 26, pp. 6533–6540, 2009.

[100] A. Raza, N. Galili, S. E. Smith et al., “A phase 2 randomizedmulticenter study of 2 extended dosing schedules of oral eza-tiostat in low to intermediate-1 risk myelodysplastic syndrome,”Cancer, vol. 118, no. 8, pp. 2138–2147, 2012.

[101] S. S. Tate andA.Meister, “Serine-borate complex as a transition-state inhibitor of 𝛾-glutamyl transpeptidase,” Proceedings of theNational Academy of Sciences of the United States of America,vol. 75, no. 10, pp. 4806–4809, 1978.

[102] R. E. London and S. A. Gabel, “Development and evaluation ofa boronate inhibitor of 𝛾-glutamyl transpeptidase,” Archives ofBiochemistry and Biophysics, vol. 385, no. 2, pp. 250–258, 2001.

[103] L. Han, J. Hiratake, A. Kamiyama, and K. Sakata, “Design,synthesis, and evaluation of 𝛾-phosphono diester analogues ofglutamate as highly potent inhibitors and active site probes of 𝛾-glutamyl transpeptidase,” Biochemistry, vol. 46, no. 5, pp. 1432–1447, 2007.

[104] P. Fidias and S. Novello, “Strategies for prolonged therapy inpatients with advanced non-small-cell lung cancer,” Journal ofClinical Oncology, vol. 28, no. 34, pp. 5116–5123, 2010.

[105] U. A. Matulonis, N. S. Horowitz, S. M. Campos et al., “PhaseII study of carboplatin and pemetrexed for the treatment ofplatinum-sensitive recurrent ovarian cancer,” Journal of ClinicalOncology, vol. 26, no. 35, pp. 5761–5766, 2008.

[106] D. M. Townsend, C. J. Pazoles, and K. D. Tew, “NOV-002, amimetic of glutathione disulfide,” Expert Opinion on Investiga-tional Drugs, vol. 17, no. 7, pp. 1075–1083, 2008.

[107] A. J. Montero and J. Jassem, “Cellular redox pathways as atherapeutic target in the treatment of cancer,”Drugs, vol. 71, no.11, pp. 1385–1396, 2011.

[108] D. M. Townsend and K. D. Tew, “Pharmacology of a mimeticof glutathione disulfide, NOV-002,” Biomedicine and Pharma-cotherapy, vol. 63, no. 2, pp. 75–78, 2009.

[109] A. J.Montero, C.M.Diaz-Montero, Y. E. Deutsch et al., “Phase 2study of neoadjuvant treatment with NOV-002 in combinationwith doxorubicin and cyclophosphamide followed by docetaxelin patients with HER-2 negative clinical stage II-IIIc breastcancer,” Breast Cancer Research and Treatment, vol. 132, no. 1,pp. 215–223, 2012.

[110] Y. Zhang, P. Talalay, C. G. Cho, and G. H. Posner, “A majorinducer of anticarcinogenic protective enzymes from broc-coli: isolation and elucidation of structure,” Proceedings of theNational Academy of Sciences of the United States of America,vol. 89, no. 6, pp. 2399–2403, 1992.

[111] D. Ren, N. F. Villeneuve, T. Jiang et al., “Brusatol enhancesthe efficacy of chemotherapy by inhibiting the Nrf2-mediateddefense mechanism,” Proceedings of the National Academy ofSciences of the United States of America, vol. 108, no. 4, pp. 1433–1438, 2011.


[112] L. Zhan, H. Zhang, Q. Zhang et al., “Regulatory role of KEAP1and NRF2 in PPARgamma expression and chemoresistancein human non-small-cell lung carcinoma cells,” Free RadicalBiology and Medicine, vol. 53, no. 4, pp. 758–768, 2012.

[113] J. Fang, T. Sawa, T. Akaike, K. Greish, and H.Maeda, “Enhance-ment of chemotherapeutic response of tumor cells by a hemeoxygenase inhibitor, pegylated zinc protoporphyrin,” Interna-tional Journal of Cancer, vol. 109, no. 1, pp. 1–8, 2004.

[114] J. Fang, T. Sawa, T. Akaike et al., “In vivo antitumor activityof pegylated zinc protoporphyrin: targeted inhibition of hemeoxygenase in solid tumor,” Cancer Research, vol. 63, no. 13, pp.3567–3574, 2003.

[115] D. Cen, D. Brayton, B. Shahandeh, F. L. Meyskens, and P.J. Farmer, “Disulfiram facilitates intracellular Cu uptake andinduces apoptosis in human melanoma cells,” Journal of Medic-inal Chemistry, vol. 47, no. 27, pp. 6914–6920, 2004.

[116] J. P. Fruehauf and F. L. Meyskens III, “Reactive oxygen species:a breath of life or death?” Clinical Cancer Research, vol. 13, no.3, pp. 789–794, 2007.

[117] J. Lu, E. H. Chew, and A. Holmgren, “Targeting thioredoxinreductase is a basis for cancer therapy by arsenic trioxide,”Proceedings of the National Academy of Sciences of the UnitedStates of America, vol. 104, no. 30, pp. 12288–12293, 2007.

[118] J. Dai, R. S. Weinberg, S. Waxman, and Y. Jing, “Malignant cellscan be sensitized to undergo growth inhibition and apoptosis byarsenic trioxide through modulation of the glutathione redoxsystem,” Blood, vol. 93, no. 1, pp. 268–277, 1999.

[119] H. Maeda, S. Hori, H. Ohizumi et al., “Effective treatment ofadvanced solid tumors by the combination of arsenic trioxideand L-buthionine-sulfoximine,” Cell Death and Differentiation,vol. 11, no. 7, pp. 737–746, 2004.

[120] V. I. Lushchak, “Glutathione homeostasis and functions: poten-tial targets for medical interventions,” Journal of Amino Acids,vol. 2012, Article ID 736837, 26 pages, 2012.

[121] K. H. Cowan, G. Batist, and A. Tulpule, “Similar biochemicalchanges associated with multidrug resistance in human breastcancer cells and carcinogen-induced resistance to xenobioticsin rats,” Proceedings of the National Academy of Sciences of theUnited States of America, vol. 83, no. 24, pp. 9328–9332, 1986.

[122] J. D. Hayes and M. McMahon, “NRF2 and KEAP1 mutations:permanent activation of an adaptive response in cancer,” Trendsin Biochemical Sciences, vol. 34, no. 4, pp. 176–188, 2009.

[123] J. M. Maher, M. Z. Dieter, L. M. Aleksunes et al., “Oxidativeand electrophilic stress inducesmultidrug resistance-associatedprotein transporters via the nuclear factor-E2-related factor-2transcriptional pathway,” Hepatology, vol. 46, no. 5, pp. 1597–1610, 2007.

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